Neural stimulation with transient response between doses

ABSTRACT

In various method embodiments for operating an implantable neural stimulator to deliver a neural stimulation therapy to an autonomic neural target, the method comprises using the implantable neural stimulator to deliver the neural stimulation therapy to the autonomic neural target, and evaluating an evoked response to the neural stimulation bursts. The neural stimulation therapy includes a plurality of neural stimulation bursts where each neural stimulation burst includes a plurality of neural stimulation pulses and successive neural stimulation bursts are separated by a time without neural stimulation pulses. Evaluating the evoked response includes sensing the evoked response to the neural stimulation bursts where sensing the evoked response includes sensing at least one physiological parameter affected by the neural stimulation bursts, comparing the sensed evoked response against a baseline, and determining if the evoked response substantially returns to the baseline between neural stimulation bursts.

CLAIM OF PRIORITY

This application is a continuation of U.S. application Ser. No.15/171,526, filed Jun. 2, 2016, which is a continuation of U.S.application Ser. No. 14/842,154, filed Sep. 1, 2015, now issued as U.S.Pat. No. 9,504,833, which is a continuation of U.S. application Ser. No.13/086,806, filed Apr. 14, 2011, now issued as U.S. Pat. No. 9,126,044,which claims the benefit of priority under 35 U.S.C. §119(e) of U.S.Provisional Patent Application Ser. No. 61/324,532, filed on Apr. 15,2010, each of which is herein incorporated by reference in its entirety.

TECHNICAL FIELD

This application relates generally to medical devices and, moreparticularly, to systems, devices and methods for delivering neuralstimulation to modulate autonomic activity.

BACKGROUND

Neural stimulation has been proposed as a therapy for a number ofconditions. Examples of neural stimulation therapies include neuralstimulation therapies for respiratory problems such as sleep disorderedbreathing, blood pressure control such as to treat hypertension, cardiacrhythm management, myocardial infarction and ischemia, heart failure,epilepsy, depression, pain, migraines, eating disorders, obesity,inflammatory diseases, and movement disorders. Some current and proposedneural stimulation therapies are chronic therapies delivered for periodson the order of minutes, days, weeks, months and years. If the neuralstimulation therapy is associated with an undesired response, theundesirability of the response may be exacerbated because of the chronicnature of the therapy. For example, the undesired response may havelong-term consequences for the health or quality of life for thepatient. It is thus desirable to reduce, minimize or eliminate undesiredresponses to neural stimulation therapies.

SUMMARY

In various method embodiments for operating an implantable neuralstimulator to deliver a neural stimulation therapy to an autonomicneural target, the method comprises using the implantable neuralstimulator to deliver the neural stimulation therapy to the autonomicneural target, and evaluating an evoked response to the neuralstimulation bursts. The neural stimulation therapy includes a pluralityof neural stimulation bursts where each neural stimulation burstincludes a plurality of neural stimulation pulses and successive neuralstimulation bursts are separated by a time without neural stimulationpulses. Evaluating the evoked response includes sensing the evokedresponse to the neural stimulation bursts where sensing the evokedresponse includes sensing at least one physiological parameter affectedby the neural stimulation bursts, comparing the sensed evoked responseagainst a baseline, and determining if the evoked response substantiallyreturns to the baseline between neural stimulation bursts.

Various device embodiments for delivering a neural stimulation therapyto an autonomic neural target of a patient comprise a neural stimulator,a memory, a controller, a sensor, and a response extractor. The neuralstimulator is configured to generate stimulation energy to stimulate theautonomic neural target. The memory has a programmed neural stimulationtherapy stored therein. The therapy includes a plurality of programmableneural stimulation parameters for use in controlling a dose of theneural stimulation therapy. The neural stimulation therapy includes aplurality of neural stimulation bursts, each burst includes a pluralityof neural stimulation pulses, and successive bursts are separated by atime without neural stimulation pulses. The controller is configured tocommunicate with the memory and the neural stimulator to control theneural stimulation therapy using the programmable parameters. The sensoris adapted to sense at least one physiological parameter indicative ofan evoked response to the neural stimulation therapy. The responseextractor is configured to receive a time series of parameter data fromthe sensor and to extract evoked response data from the time series ofparameter data and configured to determine if the evoked response datasubstantially returns to the baseline between neural stimulation bursts.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Thescope of the present invention is defined by the appended claims andtheir equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments are illustrated by way of example in the figures ofthe accompanying drawings. Such embodiments are demonstrative and notintended to be exhaustive or exclusive embodiments of the presentsubject matter.

FIG. 1. illustrates a representation of intermittent neural stimulation(INS).

FIGS. 2A-2D illustrate representations of direct and reflex responses toneural stimulation of a physiological signal modulated by the ANS.

FIG. 3 illustrates a train of neural stimulation bursts used to provideparasympathetic stimulation.

FIGS. 4A, 4B, 5A and 5B illustrate applications of the neuralstimulation illustrated in FIG. 3 to a target to elicit an ANS effect onheart rate (HR) or blood pressure (BP).

FIGS. 6A-6C illustrate various embodiments for monitoring a response toan intermittent NS burst.

FIG. 7 illustrates various embodiments for monitoring a response to anintermittent NS therapy.

FIGS. 8 and 9 illustrate various methods for delivering neuralstimulation therapy and evaluating an evoked response to intermittent NSpulses, according to various embodiments.

FIG. 10 illustrates some examples of programmable parameters that may beused and modified based on a detected evoked response to theintermittent neural stimulation.

FIG. 11 illustrates a system embodiment configured to extract an evokedresponse and control stimulation using the extracted response.

FIG. 12 illustrates an embodiment of the response extractor.

FIG. 13 illustrates an example of signal averaging measurements used invarious embodiments, where the first panel illustrates the measurementsof systolic pressure during vagal stimulation cycles and the secondpanel illustrates signal averaging of 30 one minute samples of signaldata.

FIG. 14 illustrates an example of using a boxcar search, according tovarious embodiments, to find an end of the evoked response to neuralstimulation.

FIG. 15 illustrates a neural stimulator device embodiment adapted todeliver intermittent neural stimulation therapy, according to variousembodiments.

FIG. 16 illustrates an implantable medical device (IMD) having a neuralstimulation (NS) component and a cardiac rhythm management (CRM)component according to various embodiments of the present subjectmatter.

FIG. 17 shows a system diagram of an embodiment of amicroprocessor-based implantable device, according to variousembodiments.

FIG. 18 illustrates a system including an implantable medical device(IMD) and an external system or device, according to various embodimentsof the present subject matter.

FIG. 19 illustrates a system including an external device, animplantable neural stimulator (NS) device and an implantable cardiacrhythm management (CRM) device, according to various embodiments of thepresent subject matter.

FIGS. 20-23 illustrate system embodiments adapted to provide vagalstimulation.

FIG. 24 is a block diagram illustrating an embodiment of an externalsystem.

FIGS. 25-27 illustrate preclinical study results.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.The following detailed description is, therefore, not to be taken in alimiting sense, and the scope is defined only by the appended claims,along with the full scope of legal equivalents to which such claims areentitled.

The present subject matter refers to intermittent neural stimulation(INS) of the autonomic nervous system (ANS), and further refers tosystems and methods to control transient ANS responses caused directlyand reflexively by the INS. Various embodiments of the present subjectmatter provide intermittent neural stimulation as a pattern of on andoff periods of stimulation that evokes direct and reflex responsesduring the on period that diminish to baseline (i.e., wash out) duringthe off period. Responses that wash out between INS periods are calledtransient responses. A direct response is the immediate effect of ANStargets directly stimulated by the INS. A reflex response is a secondaryeffect of ANS reflex circuits stimulated by the direct response.Collectively, the transient direct and reflex ANS responses caused bythe INS shall be referred to as the evoked response. The evoked responsemay have therapeutic and undesirable effects. The combination of directand reflex ANS responses may be therapeutic. It is currently believedthat it is desirable to control these direct and reflex responses toprovide a transient balanced effect. By way of example and notlimitation, it is believed that it is desirable for reflex responses toreturn to a baseline between stimulation bursts of an autonomic INStherapy. Additionally, for certain therapies, some direct physiologicaleffects of neural stimulation such as heart rate and blood pressurechanges may be undesirable, and it is believed to be desirable tocontrol these undesired effects to be transient so that they return tobaseline between stimulations. The present subject matter provides ameans to monitor or measure ANS responses for an autonomic modulationtherapy delivered with intermittent neural stimulation pulses, as a wayof promoting transient balanced effects of the ANS and/or as a way ofpromoting the avoidance of undesirable physiological effects of the ANS.For example, the present subject matter can detect the transient evokedresponse and the return of the evoked response to a baseline beforedelivering a subsequent stimulation burst. The stimulation of the ANScan be controlled to allow the direct and reflex effects of neuralstimulation to substantially return to baseline between stimulationperiods.

FIG. 1. illustrates a representation of intermittent neural stimulation(INS). The figure diagrammatically shows the time-course of a neuralstimulation that alternates between intervals of stimulation being ON,when one stimulation pulse or a set of grouped stimulation pulses (i.e.,a burst) is delivered, and intervals of stimulation being OFF, when nostimulation pulses are delivered. The duration of the stimulation ONinterval is sometimes referred to as the stimulation duration or burstduration. The start of a stimulation ON interval is a temporal referencepoint NS Event. The time interval between successive NS Events is theINS Interval, which is sometimes referred to as the stimulation periodor burst period. For an application of neural stimulation to beintermittent, the stimulation duration (i.e., ON interval) must be lessthan the stimulation period (i.e., INS Interval) when the neuralstimulation is being applied. The duration of the OFF intervals of INSare controlled by the durations of the ON interval and the INS Interval.The duration of the ON interval relative to the INS Interval (e.g.,expressed as a ratio) is sometimes referred to as the duty cycle of theINS.

To assist the reader, a brief discussion of ANS physiology and thedirect/reflex response to ANS modulation by INS is provided below,followed by a discussion of monitoring ANS response(s) to intermittentANS stimulation and a discussion of various device and systemembodiments.

ANS Physiology

The automatic nervous system (ANS) regulates “involuntary” organs, whilethe contraction of voluntary (skeletal) muscles is controlled by somaticmotor nerves. Examples of involuntary organs include respiratory anddigestive organs, and also include blood vessels and the heart. Often,the ANS functions in an involuntary, reflexive manner to regulateglands, to regulate muscles in the skin, eye, stomach, intestines andbladder, and to regulate cardiac muscle and the muscle around bloodvessels, for example.

The ANS includes the sympathetic nervous system and the parasympatheticnervous system. The sympathetic nervous system is affiliated with stressand the “fight or flight response” to emergencies. Among other effects,the “fight or flight response” increases blood pressure and heart rateto increase skeletal muscle blood flow, and decreases digestion toprovide the energy for “fighting or fleeing.” The parasympatheticnervous system is affiliated with relaxation and the “rest and digestresponse” which, among other effects, decreases blood pressure and heartrate, and increases digestion to conserve energy. The ANS maintainsnormal internal function and works with the somatic nervous system.

The heart rate and force is increased when the sympathetic nervoussystem is stimulated (the parasympathetic system in inhibited), and isdecreased when the sympathetic nervous system is inhibited (theparasympathetic nervous system is stimulated). An afferent nerve conveysimpulses toward a nerve center. An efferent nerve conveys impulses awayfrom a nerve center.

Stimulating the sympathetic and parasympathetic nervous systems can haveeffects other than heart rate and blood pressure. For example,stimulating the sympathetic nervous system dilates the pupil, reducessaliva and mucus production, relaxes the bronchial muscle, reduces thesuccessive waves of involuntary contraction (peristalsis) of the stomachand the motility of the stomach, increases the conversion of glycogen toglucose by the liver, decreases urine secretion by the kidneys, andrelaxes the wall and closes the sphincter of the bladder. Stimulatingthe parasympathetic nervous system (inhibiting the sympathetic nervoussystem) constricts the pupil, increases saliva and mucus production,contracts the bronchial muscle, increases secretions and motility in thestomach and large intestine, increases digestion in the small intestine,increases urine secretion, and contracts the wall and relaxes thesphincter of the bladder. The functions associated with the sympatheticand parasympathetic nervous systems are many and can be complexlyintegrated with each other.

As identified above the sympathetic and parasympathetic systems provideopposite effects. The ANS reflexes tend to compensate for these effects,returning the physiologic system to an autonomic balance. For example,an event that causes an increase in sympathetic activity and/or decreasein parasympathetic activity causes an increase in sympathetic tone,which tends to cause the ANS reflexes to increase parasympatheticactivity and/or decrease sympathetic activity to decrease thesympathetic tone after the event ends. Similarly, an event that causes adecrease in sympathetic activity and/or increase in parasympatheticactivity causes an increase in parasympathetic tone, which tends tocause the ANS reflexes to decrease parasympathetic activity and/orincrease sympathetic activity to decrease the parasympathetic tone afterthe event ends.

Direct Responses and Reflex Responses to ANS Modulation

FIGS. 2A-2D illustrate representations of direct and reflex responses toneural stimulation of a physiological signal modulated by the ANS, e.g.,heart rate. Such direct and reflex responses of the physiological signaltypically are opposite, because the ANS functions to maintain a balanceof opposing parasympathetic and sympathetic physiological effects.Direct parasympathetic responses and sympathetic reflex responses areillustrated within this document as an example. The present subjectmatter is also applicable to direct sympathetic responses andparasympathetic reflex responses. The portion of the signal below theinitial baseline 201 represents the direct response 202 to neuralstimulation pulses (NS pulse) that elicit a parasympathetic response,and the portion of the signal above the straight line 201 represents thesympathetic reflex response 204 after the direct response 202 ends.Various stimulation parameters can be selected to provide the desireddirect and reflex response. FIG. 2A illustrates a period of INS whenfive neural stimulation ON periods (NS) are delivered where each NSevokes a direct response 202 only, which does not return to the initialbaseline 201 between successive NS. This illustrates a direct responsethat is not transient during the INS. At each NS, the direct response202 peaks below the initial baseline 201 followed by a recovery 203 backtoward baseline 201. However this recovery does not return to baseline201 before the next NS. As a result of the incomplete direct responserecovery between successive NS, the subsequent signal baseline 205progressively shifts lower below the initial baseline 201 after each NSof the INS. It is believed the effect of non-transient direct responsesaccumulating over repeated stimulations during INS may be undesirable inmany clinical applications of neural stimulation. FIG. 2B illustrates aperiod of INS similar to FIG. 2A, except the stimulation parameters havebeen adjusted to cause the direct response 202 to return to the initialbaseline 201 between successive NS. This illustrates a direct responsethat is transient during the INS. FIG. 2C illustrates a period of INSwhere each NS evokes a direct response 202 and a reflex response 204,which does not return to the initial baseline 201 between successive NS.This illustrates a reflex response that is not transient during the INS.At each NS, the direct response 202 peaks below the initial baseline 201followed by a reflex response 204 that peaks above baseline 201 followedby a recovery 203 back toward baseline 201. However this recovery doesnot return to baseline 201 before the next NS. As a result of theincomplete reflex response recovery between successive NS, thesubsequent signal baseline 206 progressively shifts higher above theinitial baseline 201 after each NS of the INS. It is believed the effectof non-transient reflex responses accumulating over repeatedstimulations during INS may be undesirable in many clinical applicationsof neural stimulation FIG. 2D illustrates a period of INS similar toFIG. 2C, except the stimulation parameters have been adjusted to causethe reflex response 204 to return to the initial baseline 201 betweensuccessive NS. This illustrates a reflex response that is transientduring the INS. Some of the parameters that can be adjusted include, butare not limited to, the magnitude and duration of the stimulation pulse,the location of the stimulation, and the timing and duration of burstsof neural stimulation in a therapy that intermittently delivers neuralstimulation bursts. Some embodiments modulate efferent and/or afferentnerve activity. The desired parameters can be selected based onempirical data, or based on a neural stimulation test routine performedat the time of the implantation of a neural stimulation device. Forexample, studies have indicated that neural stimulation bursts deliveredusing a nerve cuff electrode to the vagus nerve in the cervical region,where the duration of the burst is approximately 10 seconds and thebursts are repeated once every minute, and where the electrical pulseshave approximately a 1 mA current and a frequency of about 20 Hz,provide a desirable transient direct and reflex response to the neuralstimulation.

FIG. 3 illustrates a train of neural stimulation bursts used to provideparasympathetic stimulation. Each burst includes a plurality of pulses(not illustrated) within the burst. In the illustration, each burst hasan equal duration (e.g. on the order of 10 seconds) and the bursts areseparated by a burst period (e.g. on the order of one minute). Theduration and/or burst period may be adjusted during the therapy toadjust the therapy dose and the transient evoked response. The dose andtransient evoked response may be adjusted by changing the amplitude,pulse frequency, and/or pulse width of the neural stimulation pulseswithin the burst.

FIGS. 4A, 4B, 5A and 5B illustrate applications of the neuralstimulation illustrated in FIG. 3 to a target to elicit an ANS effect onheart rate (HR) or blood pressure (BP). Negative-going waveformsillustrated in FIGS. 4B and 5B indicate a decrease in HR or BP, such asexpected from parasympathetic stimulation, while positive-goingwaveforms indicate an increase in HR or BP, such as expected fromsympathetic stimulation. FIGS. 4A and 4B illustrate stimulationparameters adjusted to elicit a transient direct parasympathetic effect.FIGS. 5A and 5B illustrate stimulation parameters adjusted to elicittransient direct parasympathetic and transient reflex sympatheticeffects.

FIG. 4A illustrates an efferent parasympathetic target, and FIG. 4Billustrates a direct response on circulation (e.g. lowered heart rate orblood pressure) to the parasympathetic stimulation pulse train, asillustrated in FIG. 3, at an efferent parasympathetic target, asillustrated in FIG. 4A. Action potentials in afferent nerves traveltoward the central nervous system (CNS), and action potentials inefferent nerves travel away from the CNS. As illustrated in FIG. 4B, thedirect response 407 attributed to the selective stimulation of theefferent pathway follows the time course of neural stimulation pulsesand returns to baseline between stimulation bursts (i.e., it istransient). The efferent stimulation in this example results in a smalldirect response in HR or BP that does not elicit a measurable reflexresponse, as indicated by immediate return to baseline of the responsefollowing termination of the stimulation burst.

FIGS. 5A and 5B illustrate an efferent parasympathetic target with anafferent parasympathetic pathway carrying signals from the target to theCNS and an efferent sympathetic pathway from the CNS carrying reflexstimulation to the target. FIG. 5B illustrates a direct and reflexresponse of the circulation (e.g., heart rate decrease then increase orblood pressure decrease then increase) to the parasympatheticstimulation pulse train, as illustrated in FIG. 3, at an efferentparasympathetic target as illustrated in FIG. 5A. As illustrated in FIG.5B, the selective stimulation of the efferent pathway provides a directresponse 507 and a reflex response 508. In this example, the efferentstimulation elicits a reflex response when baroreceptors in FIG. 5Arespond to the lowered HR or BP, sending impulses to the CNS in theafferent nerve illustrated in FIG. 5A and thereby eliciting acompensatory sympathetic reflex that increases HR and BP via impulsesconveyed from the CNS in the sympathetic efferent pathway illustrated inFIG. 5A. As illustrated in FIG. 5B, the direct response ends quicklyafter the end of the stimulation burst, whereas the reflex responsecontinues measurably after the end of the stimulation burst, and bothdirect and reflex responses return to baseline before the nextstimulation burst (i.e., they are transient).

The present subject matter is not limited to a particular mechanism, butrather monitors responses to ANS modulation to verify and, in someembodiments, control the evoked direct and reflex responses of theneural stimulation to be transient. For example, the present subjectmatter provides a means to monitor or measure INS responses, as a way ofpromoting balanced transient direct and reflex effects and/or promotingthe avoidance of undesirable physiological effects. For example, thepresent subject matter can measure the magnitudes of direct and reflexresponses and detect their washout before subsequent stimulation, andthe ANS can be stimulated to allow the direct and reflex responses ofneural stimulation to be transient.

Monitoring ANS Response to Intermittent NS Bursts

FIGS. 6A-6C illustrate various embodiments for monitoring a response toan intermittent NS burst. Multiple bursts can be analyzed, according tovarious embodiments. Each figure illustrates one neural stimulationburst among a plurality of INS stimulation bursts of a programmed NStherapy. The NS burst includes a plurality of NS pulses that arepreceded and followed by a time without NS pulses. In one embodimentillustrated in FIG. 6A, an ANS signal is monitored over time and markedwith the NS event, which is a time point with a fixed offset from thestart of the NS burst. The NS event offset from the NS burst start maybe a zero offset, a negative offset, or a positive offset depending onvarious signal analysis embodiments, although a zero offset ispreferred. The NS event divides the ANS signal into a Pre-Event Signaland a Post-Event Signal. The pre-event signal and the post-event signalcan be compared using various signal analysis embodiments, as detailedbelow, to determine which portion of the post-event signal is correlatedto the NS event. Some embodiments select INS therapy parameters toprovide that the post-event signal becomes uncorrelated to the NS eventbefore the next intermittent NS burst, making the response to NStransient. In one embodiment illustrated in FIG. 6B, the pre-eventsignal contains a pre-event baseline and the post-event signal containsan evoked response and a post-event baseline. In this example, the INStherapy parameters are selected so that the pre-event signal is notmeasurably influenced by (e.g., not correlated to) the immediatelypreceding NS burst during the pre-event baseline. The pre-event baselineinterval can begin anytime before the NS event when the pre-event signalis uninfluenced by the preceding NS and can end anytime before or at theNS event. The evoked response is a post-event signal correlated to theNS event that is measurably different from the pre-event baselinesignal. The difference can be determined as detailed below (e.g. signalaveraging and boxcar testing). The evoked response interval begins whenthe post-event signal deviates measurably from the pre-event baselinesignal, and it ends when the signal becomes measurably similar to thepre-event baseline signal. The post-event baseline is that portion ofthe post-event signal following the evoked response when the signal issimilar to the pre-event baseline signal. Some embodiments select INStherapy parameters to provide a post-event baseline, making the evokedresponse to each NS burst transient. In one embodiment illustrated inFIG. 6C, the evoked response is analyzed to detect and measurecomponents representative of the direct and reflex responses to NS. Inthis example, peaks in the evoked response are detected byzero-crossings in the first derivative of the evoked response signal.The initial response peak generally results from a direct response toNS. The interval from the start of the evoked response to the initialresponse peak is the initial response, which generally is representativeof the direct response of NS. After the response peak, the evokedresponse recovers toward baseline and can oscillate above and belowbaseline before recovering to baseline levels. Measurable recoveryresponse oscillations generally result from a reflex response to NS. Theinterval from the end of the initial response to the end of the evokedresponse is the recovery response, which generally is representative ofthe reflex response of NS. Recovery response oscillations indicate theoccurrence and nature of the reflex response. In some embodiments INStherapy parameters are selected to balance direct and reflex responsemagnitudes and/or durations. In some embodiments parameters are selectedto maximize or minimize either or both of the direct and reflex responsemagnitudes and/or durations. Some embodiments maximize the directresponse and minimize the reflex response, while others minimize thedirect response and maximize the reflex response. Some embodiments tryto evoke a pattern of direct and reflex responses.

FIG. 7 illustrates various embodiments for monitoring a response to anintermittent NS therapy. The figure illustrates a programmed NS therapythat includes a plurality of intermittent NS stimulation bursts depictedin the top trace “STIM”. Each NS burst includes a plurality of NS pulses(not shown), and successive NS bursts are separated by a time without NSpulses. This figure also illustrates the evaluation of the ANS responsedepicted in the bottom trace “SIGNAL” to three successive NS burststagged by NS Event markers 1, 2 and 3, each of which is a fixed offsetfrom the start of its corresponding NS burst. Various embodimentsevaluate the ANS response to all NS bursts in the therapy. Someembodiments evaluate the ANS response to an NS burst in response to adevice command (e.g. according to a schedule or in response to adetected event) or a command from a physician. FIG. 7 illustrates thateach evaluated NS event includes a pre-event signal 701 and a post-eventsignal 702. To evaluate a transient response, the pre-event signal 701is selected to start after the end of the response correlated to theimmediately preceding NS burst, and the post-event signal 702 isselected to end before the immediately following NS event marker. Asillustrated in FIG. 7, the post-event signal 702 of one evaluated NSevent can overlap with the pre-event signal 701 of a following evaluatedNS event. In evaluating a NS event, some embodiments only monitor thepost-event signal of the burst. Other embodiments monitor the pre-eventsignal before the NS event and monitor the post-event signal after theNS event. Various embodiments use the pre-event signal before the NSevent to provide a baseline response. In evaluating a NS event, someembodiments monitor the pre-event baseline before the NS event andmonitor the evoked response to the burst. Various embodiments evaluatecomponents of an evoked response corresponding to the direct and reflexresponse to NS in an effort to evoke a specific pattern of direct andreflex response, for example, to balance the transient physiologicaleffects of the NS therapy.

FIGS. 8 and 9 illustrate various methods for delivering neuralstimulation therapy and evaluating an evoked response to intermittent NSpulses, according to various embodiments. In the embodiment illustratedin FIG. 8, therapy parameters to deliver intermittent NS bursts areprogrammed into an implantable medical device at 809. At 810, theprogrammed NS therapy is delivered to an ANS target to modulate the ANS.The programmed therapy includes bursts of NS pulses. At 811, the evokedresponse is evaluated. For example, some embodiments determine if theevoked response substantially returns to a baseline before the nextburst. In some embodiments, the post-event signal that is correlated toa NS event with a defined time offset from each NS burst is evaluated,and at 812, the NS therapy parameters are adjusted if the correlatedsignal is not as desired, e.g., if it is not transient or not balancedor otherwise unacceptable as described herein. In the embodimentillustrated in FIG. 9, therapy parameters to deliver intermittent NSbursts are programmed into an implantable medical device at 909. At 910,the programmed NS therapy is delivered to an ANS target to modulate theANS. The programmed therapy includes bursts of NS pulses. At 911, anevoked response in the post-event signal correlated to a NS event with adefined time offset from each NS burst and deviating from the pre-eventsignal is evaluated; and at 912, the NS therapy parameters are adjustedif the response is not as desired, e.g., if it is not transient or notbalanced or otherwise unacceptable as described herein. In theillustrated embodiment, the evaluating the evoked response 911 includessensing one or more parameters in the pre-event signal (also referred toas a pre-stimulation sample) 913 and sensing the one or more parametersin the post-event signal (also referred to as a post-stimulation sample)914. At 915, the pre-stimulation sample and the post-stimulation sampleare compared to evaluate the evoked response.

There are a number of methods that may be used to characterize andmonitor the ANS response to the stimulation. For example someembodiments confirm that the evoked response is transient as it returnsto a baseline before a subsequent neural stimulation burst, someembodiments determine the duration of the response, some embodimentsdetermine the area under the response curve, some embodimentsautomatically search for an evoked response goal, some embodiments usesensors from other devices to confirm the response, and some embodimentsoptimize a compensatory reflex-mediated effect.

Some evoked responses are managed to be transient because they areunwanted side-effects of the NS at a level necessary for effectivetreatment outcomes (e.g. bradycardia, discomfort, ancillary musclestimulation, and the like). Some evoked responses are managed tooptimize or otherwise improve the effectiveness of the NS therapy, andsome embodiments are managed to oscillate parasympathetic andsympathetic responses to optimize or otherwise improve the effectivenessof the NS therapy.

Some embodiments use signal averaging to detect evoked responses in thepresence of background signal fluctuation. Signals from repeated INSstimulation bursts are aligned to a defined NS event and averaged overthe repeated samples, which minimizes the uncorrelated backgroundfluctuations and extracts the correlated evoked response signal. INStherapy parameters then can be adjusted to ensure that the evokedresponse is transitory and has an acceptable pattern. Examples of thistechnique are presented below.

Some embodiments use Fourier analysis to detect and measure evokedresponses. Fourier decomposition of the signal data time-series candetermine the frequency spectrum of the signal and detect whenoscillations of specific frequency are present and measure their power.These indicators can be used to optimize and control the transientresponse.

Some embodiments use autocorrelation to determine the duration of thetransitory response. Autocorrelation of the background fluctuatingsignal (without NS) will have some baseline value. However, the signalfluctuation caused by NS will have a higher (different) autocorrelationvalue for the period when the signal is affected by the NS. The signalbefore and following an NS event is subject to autocorrelation over somesample duration period. The signal before the stimulation and after thetransient response has receded to background should have anautocorrelation value reflecting only random changes in the signal. Thesignal change resulting from the NS event will have a higherautocorrelation value compared to autocorrelation of the baselinepreceding the simulation. The end of the NS transient event is detectedwhen autocorrelation of the signal following the NS event declines tothe pre-NS baseline value.

Some embodiments use cross-correlation to determine the duration of thetransitory response. A random time interval (period) of the signal has alow correlation when cross-correlated with another random time intervalof the signal when the signal fluctuations are due to randomly varyingfactors. However two time intervals, each following a NS event, areexpected to have highly correlated values because the signal shouldfluctuate similarly as part of the NS response. The signal following theNS event can be divided into a series of sequential time intervals (e.g.i=1, 2, . . . n) of a fixed duration (the duration being set accordingto expectations about how long the transitory response will last). Thecross-correlation between corresponding intervals after different NSevents [e.g., E(1,i), E(2,i), . . . E(N,i)] are expected to be highlycorrelated for intervals during which there is in fact an NS-generatedsignal response, and are expected to be uncorrelated when intervals arecompared that occur after the NS response has diminished to backgroundlevels. The last interval exhibiting significant correlation would bethe end of the transient response. The signals could be pre-filtered oraveraged to remove non-stationary fluctuations before correlation, forexample, to remove slow frequency drifts in signal levels.

Some embodiments use template matching techniques to detect and measureparticular patterns of evoked response. Templates may be stored inmemory in an implantable neural stimulator. Templates can be based onwhole signals or a collection of partial signals. Templates can be basedon a characteristic set of features extracted from the signals, forexample, the relative times of peak values, number of baseline (zero)crossings, signal slopes, and the like. Template matching can use anyavailable method known in the art. An example is correlation of thetemplate and the signal. Signals can be pre-processed by filtering andaveraging, etc, before template matching.

Some embodiments measure the area under the curve as a way to determinewhen a balanced or otherwise desirable response is obtained. Someembodiments find the end of a transient response (i.e., theduration/period of the transient response) by measuring the area underthe curve cumulatively from the NS event to each time point followingthe NS event until a time point is found where the cumulative areaapproaches zero (or another defined value). For example, the stimulationintensity/duration parameters are adjusted until the area under thecurve for a tracked physiological variable (e.g. BP or FIR) during adefined transient response period approaches a net of zero or some otherdefined net value.

Some embodiments perform an automated search over a range ofneurostimulation parameters for an evoked response goal. For example,various embodiments program and constrain the automated search behaviorto be for specified parameters alone or in combination over a definedparameter range, a defined search schedule, or a defined success/failurecriteria. Some example search methods are parameter ramps (e.g.,amplitude ramp, a stimulation duration ramp), hill climbing techniques,simulated annealing, and other algorithmic search techniques. Forexample, NS burst duration and burst interval, and/or stimulation pulseintensity and pulse frequency may be varied during a search. Differentstimulation locations (with multi-electrode configurations) andstimulation waveforms (with single or multi-electrode configurations)may be varied to change the axon (neural pathway) sets that arecaptured, to allow search over different neural pathways for an optimaltransient response.

The present subject matter is designed to allow NS to be configured toachieve long-term clinical treatment effects (outcomes) while avoidingor otherwise controlling specific transient response effects. The NStreatment effects (outcomes) can be measured by standard clinicalindicators of disease state. For example, for cardiovascularapplications, treatment success can be measured by biomarkers (BNP, ANP,TNF, SERCA, cardiac troponins, creatine kinase, MMPs, TIMPs,interleukins, plasma NE, C-reactive protein, etc.), cardiac functionalmeasurements (minimum, maximum, and mean HR, HR variability, ejectionfraction, valve regurgitation, stroke volume, systolic and diastolic BP,cardiac chamber systolic and diastolic pressures, contraction synchronyand pattern, etc.), cardiac structural measures (end-diastolic andend-systolic volumes, vessel patency/occlusion, etc), clinical measures(patient weight, six-minute walk distance, peak VO₂, hospitalizationfrequency, MI events, quality of life scores, etc.). These clinicalmeasures of the outcome of the treatment are all expected to be apparentover clinical recovery time periods, typically, weeks or months.Measures of a clinical response are distinct from measures of a NSevoked response, which various embodiments described herein activelymanage to be transient.

One of the monitored physiological event responses to the neuralstimulation, according to various embodiments, is an oscillatoryresponse corresponding to a direct effect of the neurostimulationfollowed by an opposite compensatory reflex-mediated effect. Someembodiments improve or optimize this oscillatory response. For example,various embodiments maximize the peak of the direct NS response, thereflex response, or both. Various embodiments maximize the duration ofthe direct NS response, reflex response or both. Various embodimentsminimize the duration of the direct NS response, reflex response orboth. Various embodiments perform some combination of maximizing andminimizing the direct NS or reflex response peak and/or duration. Someembodiments measure oscillations by detecting zero crossings in thefirst derivative of the response, in some cases after performingfiltering to remove high frequency oscillations. Some embodiments forgenerating and improving or optimizing a response select the stimulationparameters dependent on the baseline HR or baseline BP or other baselinephysiological measure. For example, if baseline HR is high, neuraltargets are selected to increase parasympathetic tone to decrease HR andprovide a desired direct and or indirect HR response. If baseline HR islow, neural targets are selected to increase sympathetic tone toincrease HR and provide a desired direct or indirect HR response.

Some embodiments deliver NS while controlling the evoked response of HRor BP (or other physiological variable) to be below a threshold level.For example, this permits NS to be delivered while ensuring there is nochange or only an acceptably low change in HR, BP or other monitoredphysiological parameter that is subject to transient response control. Atherapeutically effective NS level can be determined by detectingspecific evoked responses known to be associated with an effective levelof stimulation. For example, vagal stimulation configured to evokelaryngeal vibration may indicate a minimum effective therapeutic level(i.e. a minimum or lower range of levels that stimulate the A fibers ofthe vagus), and it can be measured by the device or physician to ensurethe device is set to a minimally effective level (i.e., that the deviceis still working by continuing to deliver the lower range oftherapeutically-effective stimulation). Then the device may increase thelevel of stimulation to maximize the therapy while controlling thetransient response of monitored physiological variables (i.e.,controlling unwanted transient side-effects or adjusting a transientresponse for optimal therapy). An example of controlling the evokedresponse is discussed in U.S. patent application Ser. No. 12/487,266filed Jun. 18, 2009 and entitled Systems and Methods for DeliveringVagal Nerve Stimulation, which is hereby incorporated by reference inits entirety.

Devices and Systems

FIG. 10 illustrates some examples of programmable parameters that may beused and modified based on a detected evoked response to theintermittent neural stimulation. The programmable parameters can includeparameters used to adjust the intensity of the neural stimulationtherapy, such as amplitude 1016, frequency 1017, pulse width 1018. Someembodiments adjust the neural stimulation schedule to adjust the neuralstimulation intensity. Examples of schedule parameters include therapyduration 1019 (e.g. how many minutes the INS therapy protocol isdelivered), start/stop times 1020 (e.g. when to start or stop the INStherapy protocol), stimulation period 1021 (e.g. the burst interval ofthe INS therapy protocol), stimulation train duration per stimulationperiod 1022 (e.g. the burst duration of the INS therapy protocol), dutycycle 1023 (e.g. the stimulation duration/stimulation period of the INStherapy protocol), and a ramp up and/or ramp down 1024 for the intensityof the stimulation burst. Some embodiments are designed with the abilityto operationally position a plurality of electrodes near the neuralpathway to stimulate different locations along the neural pathway toinitiate an action potential at these different locations along theneural pathway, as generally illustrated at 1025. Some embodimentschange where the nerve is stimulated to change the distance that theaction potential has to travel before inducing a response, and thuschanges the timing of the response induced by the action potential for adirect response or a reflex response. Some embodiments control whetheran efferent or afferent pathway is being stimulated, as illustratedgenerally at 1026.

The neural stimulation delivered during the duty cycle can be deliveredusing a variety of neural stimulation techniques, such as stimulationthat uses electrical, ultrasound, thermal, magnetic, light or mechanicalenergy. Electrical neural stimulation is used in this document as anexample of neural stimulation. In electrical stimulation, for example, atrain of neural stimulation pulses (current or voltage) can be deliveredduring a duty cycle of stimulation. Stimulation pulse waveforms can besquare pulses or other morphologies. Additionally, the stimulationpulses can be monophasic or biphasic pulses.

Various embodiments control neural stimulation to provide controlled,transient changes in the HR, BP and other physiological activityfollowing intermittent neurostimulation events. The following examplesare illustrated using heart rate and blood pressure signals and targets.Heart rate and blood pressure are non-exclusive examples. As is known inthe art, other physiologic parameters are affected by ANS activity. Thepresent subject matter may be implemented using other physiologicalsignals and targets. FIG. 11 illustrates a system embodiment configuredto extract an evoked response and control stimulation using theextracted response. Various device embodiments include a neuralstimulation delivery system 1127 (also referred to as a neuralstimulator), a response extractor 1128 that is capable of providingfeedback from sensors (e.g. HR sensor 1129 and/or BP sensor 1130, andothers), and a controller 1131. The neural stimulator is configured todirectly or reflexively modulate heart rate and/or blood pressure, forexample. The response extractor extracts a representation of the evokedresponse by determining how the heart rate and/or blood pressureresponse is correlated with a given intermittent neurostimulation, andthen determines parameters of the response, such as overall duration,direct and reflex response durations and magnitudes, and others. Thecontroller is configured to modulate the neurostimulation dose and/orduty cycle to provide an evoked response that is transient and/or toachieve a pre-determined evoked response pattern.

Thus, some embodiments limit the HR or BP responses evoked byintermittent NS to be transient in nature, where the HR or BP returns tothe baseline before the next stimulation burst is delivered. That is,the HR and BP will return on average to pre-stimulation levels betweensuccessive intermittent stimulations. This does not preclude long-termprogression in HR or BP, which may be a therapeutic goal ofchronically-applied NS. The difference is that transient changes occuron the order of the intermittent NS duty cycle (e.g., minutes), whilelong-term therapeutic changes occur on the order of chronic clinicalchanges (e.g., days or months). Other embodiments similarly controlother physiological targets and signals.

HR sensors can be used to record HR time series signals, and BP sensorscan be used to record BP time series signals. A neural stimulation (NS)event (e.g., an intermittent burst of given amplitude, duration,location, polarity, etc.) may evoke a perturbation in HR or BP that hasa predictable and repeatable pattern and duration, referred to herein asthe evoked response. Time series decomposition can extract the evokedresponse that is correlated with intermittent NS events of a given dose.In particular the duration of the evoked response can be determined bydetermining the length of time the correlated perturbations due to a NSevent persist. The duration of this evoked response is the time requiredfor changes in HR or BP due to the NS event to wash out, that is, returnto baseline. Once this is determined by a response extractor for a givenNS dose, the INS duty cycle can be adapted by the controller to ensurethat any changes in HR or BP due to intermittent NS events aretransient. This avoids clinical risks that may be caused by persistentadverse changes in HR or BP during NS therapy (e.g., causing excessivebradycardia in heart failure patients). Also the pattern of the evokedresponse can be analyzed to determine and measure direct and reflexresponse components. For example as illustrated in FIG. 6C, the initialresponse to the NS burst can be detected by the initial response peak,which generally corresponds to the direct response. This is followed bythe recovery response, when the initial response recovers to baseline,either directly or with one or more response oscillations. The presenceof oscillations in the recovery response is an indication of reflexresponses. The magnitudes of the direct and reflex responses can beestimated by their corresponding response peaks detected aszero-crossings in the response first derivative, and their durations canbe estimated by the interval between the first derivative peakscorresponding to the slope changes on either side of their responsepeaks. The controller may control features of the stimulation protocolto control the magnitude, duration, and other patterns of the direct andreflex response to the stimulation.

The effect of the neural stimulation on HR or BP is controlled by the NSdose, which consists of a complex set of variables, including electrodedesign, stimulation site, pulse amplitude, width and phase, pulse burstduration and pattern, stimulation timing, and the like. The selection ofNS dose depends on the therapeutic application of the device. In someapplications, the NS dose may be selected to decrease or increase HR orBP transiently by directly stimulating neural pathways that control HRor BP. This in turn may result in compensatory reflex changes in HR orBP after the NS event ends. In such cases, the NS event may cause anoscillation of HR or BP that lasts for several seconds or minutes. Theseare oscillatory evoked responses. They may be preferred in someapplications of the device to deliver a combination of directlystimulated and reflex changes in ANS activity. By altering the NS dose,the device can control the magnitude, pattern, and duration of the HR orBP evoked responses. A device response extractor can measure theseevoked response parameters to be used by a controller to adapt the NSdose to achieve a preferred or optimal evoked response.

HR and BP sensors 1129 and 1130 provide a continuous stream of HR and BPsignal data to the response extractor 1128. This data stream can bedigitized into a discrete time series for analysis. The responseextractor 1128 is notified of each intermittent NS event from the NSdelivery system 1127. The response extractor uses these events toprocess the signal time series to detect correlated responses in thesignal following an event. Multiple NS events are analyzed to extract acorrelated response from background (uncorrelated) signal fluctuations.The extracted correlated response is then quantified to provide evokedresponse data, such as response duration, to the controller. Thecontroller 1131 uses these data according to programmed parameters tocontrol the duty cycle and/or the dose of the neurostimulation. Forexample, the controller may be programmed to adjust the INS interval tobe greater than or equal to the duration of the evoked response, thusensuring that HR or BP responses caused by each NS event return tobackground levels before the next NS is delivered. The controller may beprogrammed to adjust the NS dose until the evoked response data matchprogrammed criteria, such as a minimum or maximum duration or a minimumor maximum response level, or many other possibilities. The controllerprovides search parameters to the response extractor to control itsfunctions. For example, the controller may set search criteria or searchwindows for the extraction algorithms, or request which evoked responsedata are to be extracted, among other possibilities.

FIG. 12 illustrates an embodiment of the response extractor 1228.Continuous analog signals from the HR or BP sensors are converted todigitized time series at signal digitizing 1229. These in turn areprocessed by signal parsing 1230 where the time series are parsed intoevent samples. The time series are parsed into event samples with atemporal sampling window aligned to a NS event, which is a time pointdefined by a fixed offset (usually zero) from the start of each NSburst. A sampling window may be defined to start a specified time justbefore a NS event and end a specified delay following a NS event. Theevent signal 1231 from the NS delivery system and a timer 1232 may beused in providing the sampling window. The signal data inside thesampling window constitute an event sample. In one application, thesampling window is specified to be somewhat longer than the expectedevoked response time in order to ensure that the entire evoked responseis sampled.

Multiple event samples are processed at 1233. For example, someembodiments use signal averaging, and some embodiments use correlation.For example, event samples are processed by signal averaging to extractthe event-related signal response (evoked response) from backgroundsignal fluctuations. Each event sample is aligned in time at the NSevent (e.g., the time base of each sample time series is shifted so thattime zero occurs at the NS event time). Then the signal values of allthe samples at each time point are averaged. An equation for this is asfollows: For all data points tin each event sample E[s] in the set of Ssamples,

${E_{Avg}\lbrack t\rbrack} = {\frac{1}{S}{\sum\limits_{s = 1}^{S}{E\left\lbrack {s,t} \right\rbrack}}}$

where E_(Avg) is the averaged response time series. This averagingsubtracts background signal fluctuations from the signal perturbationscorrelated with the NS event. The result is an averaged time seriesrepresenting the evoked response. The evoked response is passed to theresponse analysis 1234 for feature extraction. The evoked response isprocessed to determine the response duration, according to someembodiments. This can be accomplished, for instance, with a baselineboxcar search. A baseline search box is created by determining the rangeof signal fluctuation within a time window just before the expectedstart of the evoked response associated with the NS event, for example,in the pre-event signal. That is, the search box will contain all valuesof the signal during a fixed length period prior to the start of theevoked response. Then the evoked response is searched for the firstpoint in time when the signal falls within the search box range for theentire search box duration. Parameters for this search can be set by thecontroller to establish, for example, duration of the search box, searchtolerances and limits, search starting point, and many otherpossibilities.

FIG. 13 illustrates an example of signal averaging measurements, wherethe first panel illustrates the measurements of systolic pressure duringvagal stimulation cycles and the second panel illustrates signalaveraging of 30 one minute samples of signal data. The top panel is areal-time recording of BP signals where neurostimulation events aredelivered at the arrows labeled VS. There is a background oscillation inthe signals that masks the signal changes correlated with the NS events.The bottom panel is the evoked response resulting from signal averaging30 one minute samples of signal data aligned to the NS event (VS). Thebackground oscillation in the signals is substantially reduced,revealing the average evoked response. This evoked response consists ofan initial peak decrease in BP (representative of the direct response)followed by two peak increase oscillations in BP (representative ofmultiple reflex responses) and recovery to pre-stimulation baselinelevels before the next stimulation (by around 40 seconds on therecording).

FIG. 14 illustrates an example of using a boxcar search to find an endof the evoked response to neural stimulation. A baseline search box isdetermined to find the signal fluctuation range prior to the neuralstimulation event and the estimated evoked response. This search box isswept forward in time through the signal until the signal is within thesearch box range during the entire search box duration (at the boxindicated by Range Match). The point in time when this occurs is thedefined end of the evoked response.

FIG. 15 illustrates a neural stimulator device embodiment adapted todeliver intermittent neural stimulation therapy, according to variousembodiments. The illustrated device 1535 can be an implantable device oran external device. The illustrated device includes a neural stimulationdelivery system 1536 adapted to deliver a neural stimulation signal tothe neural stimulation electrode(s) or transducer(s) 1537 to deliver theneural stimulation therapy. Examples of neural stimulation electrodesinclude nerve cuff electrodes, intravascularly placed electrodes, andtranscutaneous electrodes. Examples of neural stimulation transducersinclude ultrasound, light and magnetic energy transducers. Someembodiments deliver neural stimulation without monitoring the directresponse to the stimulation. For example, some embodiments may deliverstimulation without attempting to drive a specific change in heart ratefor each stimulation burst, and only limit the change to be transient.Some embodiments deliver therapy using a closed-loop control system,where one or more physiologic parameters, also referred to herein astherapy inputs, are sensed and used as feedback to control the neuralstimulation intensity to drive the one or more physiologic parameters toa target value or a target range of values. A controller 1538 receivestherapy inputs 1539, and appropriately controls the neural stimulationtherapy delivery system 1536 using the therapy inputs 1539 to providethe appropriate neural stimulation signal to theelectrode(s)/transducer(s) that results in a desired intensity of neuralstimulation, and results in a desired direct and reflex stimulation. Theillustrated device includes a memory to store programmable parameters1540. The controller 1538 implements a neural stimulation protocol 1541using the programmable parameters to control the waveform generator 1542of the neural stimulation therapy delivery system 1536. The programmableparameters can be selected to provide the desired direct and reflexresponse to neural stimulation. The controller 1538 can control thetherapy according to programmable therapy dose, duty cycle, and searchparameters, as illustrated in FIG. 11. The controller 1538 may include aresponse extractor, such as generally illustrated in FIG. 12. Theillustrated device includes a protocol feedback input 1543, such as maybe used to either program the parameters during implant or chronicallycontrol the therapy to provide the desired direct and/or reflex responseto the neural stimulation. The input 1543 can receive a communicationfrom a device programmer, for use by a physician or patient in changingthe programmable parameters based on observed conditions. The input 1543can receive feedback from physiologic sensors used to monitor transientresponses at the beginning and/or end of the neural stimulation train.Examples of such sensors used to provide feedback for the transitionprotocol include, but are not limited to, heart rate and blood pressuresensors.

Patient management systems can be used to enable the patient and/ordoctor to adjust parameter(s) to compensate for undesired transientresponses, such as may be sensed by physiologic parameters and output tothe patient and/or doctor. The inputs can be provided by computers,programmers, cell phones, personal digital assistants, and the like. Thepatient can call a call center using a regular telephone, a mobilephone, or the internet. The communication can be through a repeater,similar to that used in Boston Scientific's Latitude patient managementsystem. In response, the call center (e.g. server in call center) canautomatically send information to the device to adjust or titrate thetherapy. The call center can inform the patient's physician of theevent. A device interrogation can be automatically triggered. Theresults of the device interrogation can be used to determine if and howthe therapy should be adjusted and/or titrated to improve the transientresponse. A server can automatically adjust and/or titrate the therapyusing the results of the device interrogation. Medical staff can reviewthe results of the device interrogation, and program the device throughthe remote server to provide the desired therapy adjustments and/ortitrations. The server can communicate results of the deviceinterrogation to the patient's physician, who can provide input ordirection for adjusting and/or titrating the therapy.

FIG. 16 illustrates an implantable medical device (IMD) 1644 having aneural stimulation (NS) component 1645 and a cardiac rhythm management(CRM) component 1646 according to various embodiments of the presentsubject matter. The illustrated device includes a controller 1647 andmemory 1648. According to various embodiments, the controller includeshardware, software, firmware or a combination thereof to perform theneural stimulation and CRM functions. For example, the programmedtherapy applications discussed in this disclosure are capable of beingstored as computer-readable instructions embodied in memory and executedby a processor. For example, therapy schedule(s) and programmableparameters can be stored in memory. According to various embodiments,the controller includes a processor to execute instructions embedded inmemory to perform the neural stimulation and CRM functions. Theillustrated neural stimulation therapy 1649 can include various neuralstimulation therapies, such as a therapy for ventricular remodeling.Various embodiments include CRM therapies 1650, such as bradycardiapacing, anti-tachycardia therapies such as ATP, defibrillation andcardioversion, and cardiac resynchronization therapy (CRT). Theillustrated device further includes a transceiver 1651 and associatedcircuitry for use to communicate with a programmer or another externalor internal device. Various embodiments include a telemetry coil.

The CRM therapy section 1646 includes components, under the control ofthe controller, to stimulate a heart and/or sense cardiac signals usingone or more electrodes. The illustrated CRM therapy section includes apulse generator 1652 for use to provide an electrical signal through anelectrode to stimulate a heart, and further includes sense circuitry1653 to detect and process sensed cardiac signals. An interface 1654 isgenerally illustrated for use to communicate between the controller 1647and the pulse generator 1652 and sense circuitry 1653. Three electrodesare illustrated as an example for use to provide CRM therapy. However,the present subject matter is not limited to a particular number ofelectrode sites. Each electrode may include its own pulse generator andsense circuitry. However, the present subject matter is not so limited.The pulse generating and sensing functions can be multiplexed tofunction with multiple electrodes.

The NS therapy section 1645 includes components, under the control ofthe controller, to stimulate a neural stimulation target and/or senseparameters associated with nerve activity or surrogates of nerveactivity such as blood pressure, heart rate and respiration. Threeinterfaces 1655 are illustrated for use to provide neural stimulation.However, the present subject matter is not limited to a particularnumber interfaces, or to any particular stimulating or sensingfunctions. Pulse generators 1656 are used to provide electrical pulsesto transducer or transducers for use to stimulate a neural stimulationtarget. According to various embodiments, the pulse generator includescircuitry to set, and in some embodiments change, the amplitude of thestimulation pulse, the pulse width of the stimulation pulse, thefrequency of the stimulation pulse, the burst frequency of the pulse,and the morphology of the pulse such as a square wave, sinusoidal wave,and waves with desired harmonic components. Sense circuits 1657 are usedto detect and process signals from a sensor, such as a sensor of nerveactivity, blood pressure, respiration, and the like. The interfaces 1655are generally illustrated for use to communicate between the controller1647 and the pulse generator 1656 and sense circuitry 1657. Eachinterface, for example, may be used to control a separate lead. Variousembodiments of the NS therapy section only include a pulse generator tostimulate a neural target. The illustrated device further includes aclock/timer 1658, which can be used to deliver the programmed therapyaccording to a programmed stimulation protocol and/or schedule. Thecontroller illustrated in FIG. 16 may include a response extractor, suchas generally illustrated in FIG. 12. The controller illustrated in FIG.16 also can control the therapy according to programmable therapy dose,duty cycle, and search parameters, as illustrated in FIG. 11.

FIG. 17 shows a system diagram of an embodiment of amicroprocessor-based implantable device, according to variousembodiments. The controller of the device is a microprocessor 1759 whichcommunicates with a memory 1760 via a bidirectional data bus. Thecontroller could be implemented by other types of logic circuitry (e.g.,discrete components or programmable logic arrays) using a state machinetype of design. As used herein, the term “circuitry” should be taken torefer to either discrete logic circuitry or to the programming of amicroprocessor. Shown in the figure are three examples of sensing andpacing channels designated “A” through “C” comprising bipolar leads withring electrodes 1761A-C and tip electrodes 1762A-C, sensing amplifiers1763A-C, pulse generators 1764A-C, and channel interfaces 1765A-C. Eachchannel thus includes a pacing channel made up of the pulse generatorconnected to the electrode and a sensing channel made up of the senseamplifier connected to the electrode. The channel interfaces 1765A-Ccommunicate bidirectionally with the microprocessor 1759, and eachinterface may include analog-to-digital converters for digitizingsensing signal inputs from the sensing amplifiers and registers that canbe written to by the microprocessor in order to output pacing pulses,change the pacing pulse amplitude, and adjust the gain and thresholdvalues for the sensing amplifiers. The sensing circuitry of thepacemaker detects a chamber sense, either an atrial sense or ventricularsense, when an electrogram signal (i.e., a voltage sensed by anelectrode representing cardiac electrical activity) generated by aparticular channel exceeds a specified detection threshold. Pacingalgorithms used in particular pacing modes employ such senses to triggeror inhibit pacing. The intrinsic atrial and/or ventricular rates can bemeasured by measuring the time intervals between atrial and ventricularsenses, respectively, and used to detect atrial and ventriculartachyarrhythmias.

The electrodes of each bipolar lead are connected via conductors withinthe lead to a switching network 1766 controlled by the microprocessor.The switching network is used to switch the electrodes to the input of asense amplifier in order to detect intrinsic cardiac activity and to theoutput of a pulse generator in order to deliver a pacing pulse. Theswitching network also enables the device to sense or pace either in abipolar mode using both the ring and tip electrodes of a lead or in aunipolar mode using only one of the electrodes of the lead with thedevice housing (can) 1767 or an electrode on another lead serving as aground electrode. Some embodiments provide a shock pulse generator 1768interfaced to the controller for delivering a defibrillation shock viashock electrodes 1769 and 1770 to the atria or ventricles upon detectionof a shockable tachyarrhythmia.

Neural stimulation channels, identified as channels D and E, areincorporated into the device for delivering parasympathetic and/orsympathetic excitation and/or parasympathetic and/or sympatheticinhibition, where one channel includes a bipolar lead with a firstelectrode 1771D and a second electrode 1772D, a pulse generator 1773D,and a channel interface 1774D, and the other channel includes a bipolarlead with a first electrode 1771E and a second electrode 1772E, a pulsegenerator 1773E, and a channel interface 1774E. Other embodiments mayuse unipolar leads in which case the neural stimulation pulses arereferenced to the can or another electrode. Other embodiments may usetripolar or multipolar leads. In various embodiments, the pulsegenerator for each channel outputs a train of neural stimulation pulseswhich may be varied by the controller as to amplitude, frequency,duty-cycle, and the like. In some embodiments, each of the neuralstimulation channels uses a lead which can be intravascularly disposednear an appropriate neural target. Other types of leads and/orelectrodes may also be employed. A nerve cuff electrode may be used inplace of an intravascularly disposed electrode to provide neuralstimulation. In some embodiments, the leads of the neural stimulationelectrodes are replaced by wireless links.

The figure illustrates a telemetry interface 1775 connected to themicroprocessor, which can be used to communicate with an externaldevice. The illustrated microprocessor 1759 is capable of performingneural stimulation therapy routines and myocardial (CRM) stimulationroutines. Examples of NS therapy routines include, but are not limitedto, therapies to provide physical conditioning and therapies to treatventricular remodeling, hypertension, sleep disordered breathing, bloodpressure control such as to treat hypertension, cardiac rhythmmanagement, myocardial infarction and ischemia, heart failure, epilepsy,depression, for pain, migraines, eating disorders and obesity, andmovement disorders. The present subject matter is not limited to aparticular neural stimulation therapy. Examples of myocardial therapyroutines, but are not limited to, include bradycardia pacing therapies,anti-tachycardia shock therapies such as cardioversion or defibrillationtherapies, anti-tachycardia pacing therapies (ATP), and cardiacresynchronization therapies (CRT).

FIG. 18 illustrates a system 1876 including an implantable medicaldevice (IMD) 1877 and an external system or device 1878, according tovarious embodiments of the present subject matter. Various embodimentsof the IMD include NS functions or include a combination of NS and CRMfunctions. The IMD may also deliver biological agents and pharmaceuticalagents. The external system and the 1 MB are capable of wirelesslycommunicating data and instructions. In various embodiments, forexample, the external system and IMD use telemetry coils to wirelesslycommunicate data and instructions. Thus, the programmer can be used toadjust the programmed therapy provided by the IMD, and the 1 MB canreport device data (such as battery and lead resistance) and therapydata (such as sense and stimulation data) to the programmer using radiotelemetry, for example. The external system allows a user such as aphysician or other caregiver or a patient to control the operation ofthe IMD and obtain information acquired by the IMD. In one embodiment,the external system includes a programmer communicating with the 1 MBbi-directionally via a telemetry link. In another embodiment, theexternal system is a patient management system including an externaldevice communicating with a remote device through a telecommunicationnetwork. The external device is within the vicinity of the IMD andcommunicates with the 1 MB bi-directionally via a telemetry link. Theremote device allows the user to monitor and treat a patient from adistant location. The patient monitoring system is further discussedbelow. The telemetry link provides for data transmission from theimplantable medical device to the external system. This includes, forexample, transmitting real-time physiological data acquired by the IMD,extracting physiological data acquired by and stored in the IMD,extracting therapy history data stored in the implantable medicaldevice, and extracting data indicating an operational status of the IMD(e.g., battery status and lead impedance). The telemetry link alsoprovides for data transmission from the external system to the IMD. Thisincludes, for example, programming the IMD to acquire physiologicaldata, programming the IMD to perform at least one self-diagnostic test(such as for a device operational status), and programming the IMD todeliver at least one therapy.

FIG. 19 illustrates a system 1976 including an external device 1978, animplantable neural stimulator (NS) device 1979 and an implantablecardiac rhythm management (CRM) device 1980, according to variousembodiments of the present subject matter. Various aspects involve amethod for communicating between an NS device and a CRM device or othercardiac stimulator. In various embodiments, this communication allowsone of the devices 1967 or 1968 to deliver more appropriate therapy(i.e. more appropriate NS therapy or CRM therapy) based on data receivedfrom the other device. Additionally, the sensors from the CRM device maymonitor HR, BP, or another parameter for the transient response to theneural stimulation. Some embodiments provide on-demand communications.In various embodiments, this communication allows each of the devices todeliver more appropriate therapy (i.e. more appropriate NS therapy andCRM therapy) based on data received from the other device. Theillustrated NS device and the CRM device are capable of wirelesslycommunicating with each other, and the external system is capable ofwirelessly communicating with at least one of the NS and the CRMdevices. For example, various embodiments use telemetry coils towirelessly communicate data and instructions to each other. In otherembodiments, communication of data and/or energy is by ultrasonic means.Rather than providing wireless communication between the NS and CRMdevices, various embodiments provide a communication cable or wire, suchas an intravenously-fed lead, for use to communicate between the NSdevice and the CRM device. In some embodiments, the external systemfunctions as a communication bridge between the NS and CRM devices.

FIGS. 20-23 illustrate system embodiments adapted to provide vagalstimulation, and are illustrated as bilateral systems that can stimulateboth the left and right vagus nerve. Those of ordinary skill in the artwill understand, upon reading and comprehending this disclosure, thatsystems can be designed to stimulate only the right vagus nerve, systemscan be designed to stimulate only the left vagus nerve, and systems canbe designed to bilaterally stimulate both the right and left vagusnerves. The systems can be designed to stimulate nerve traffic(providing a parasympathetic response when the vagus is stimulated), orto inhibit nerve traffic (providing a sympathetic response when thevagus is inhibited). Various embodiments deliver unidirectionalstimulation or selective stimulation of some of the nerve fibers in thenerve.

FIG. 20 illustrates a system embodiment in which an 1 MB 2081 is placedsubcutaneously or submuscularly in a patient's chest with lead(s) 2082positioned to stimulate a vagus nerve. According to various embodiments,neural stimulation lead(s) 2082 are subcutaneously tunneled to a neuraltarget, and can have a nerve cuff electrode to stimulate the neuraltarget. Some vagus nerve stimulation lead embodiments areintravascularly fed into a vessel proximate to the neural target, anduse electrode(s) within the vessel to transvascularly stimulate theneural target. For example, some embodiments stimulate the vagus usingelectrode(s) positioned within the internal jugular vein. Otherembodiments deliver neural stimulation to the neural target from withinthe trachea, the laryngeal branches of the internal jugular vein, andthe subclavian vein. The neural targets can be stimulated using otherenergy waveforms, such as ultrasound and light energy waveforms. Otherneural targets can be stimulated, such as cardiac nerves and cardiac fatpads. The illustrated system includes leadless ECG electrodes 2083 onthe housing of the device. These ECG electrodes are capable of beingused to detect heart rate, for example.

FIG. 21 illustrates a system embodiment that includes an implantablemedical device (IMD) 2181 with satellite electrode(s) 2184 positioned tostimulate at least one neural target. The satellite electrode(s) areconnected to the IMD, which functions as the planet for the satellites,via a wireless link. Stimulation and communication can be performedthrough the wireless link. Examples of wireless links include RF linksand ultrasound links. Examples of satellite electrodes includesubcutaneous electrodes, nerve cuff electrodes and intravascularelectrodes. Various embodiments include satellite neural stimulationtransducers used to generate neural stimulation waveforms such asultrasound and light waveforms. The illustrated system includes leadlessECG electrodes on the housing of the device. These ECG electrodes 2183are capable of being used to detect heart rate, for example.

FIG. 22 illustrates an IMD 2281 placed subcutaneously or submuscularlyin a patient's chest with lead(s) 2285 positioned to provide a CRMtherapy to a heart, and with lead(s) 2282 positioned to stimulate and/orinhibit neural traffic at a neural target, such as a vagus nerve,according to various embodiments. According to various embodiments,neural stimulation lead(s) are subcutaneously tunneled to a neuraltarget, and can have a nerve cuff electrode to stimulate the neuraltarget. Some lead embodiments are intravascularly fed into a vesselproximate to the neural target, and use transducer(s) within the vesselto transvascularly stimulate the neural target. For example, someembodiments target the vagus nerve using electrode(s) positioned withinthe internal jugular vein.

FIG. 23 illustrates an IMD 2381 with lead(s) 2385 positioned to providea CRM therapy to a heart, and with satellite transducers 2384 positionedto stimulate/inhibit a neural target such as a vagus nerve, according tovarious embodiments. The satellite transducers are connected to the IMD,which functions as the planet for the satellites, via a wireless link.Stimulation and communication can be performed through the wirelesslink. Examples of wireless links include RF links and ultrasound links.Although not illustrated, some embodiments perform myocardialstimulation using wireless links. Examples of satellite transducersinclude subcutaneous electrodes, nerve cuff electrodes and intravascularelectrodes.

FIG. 24 is a block diagram illustrating an embodiment of an externalsystem 2486. The external system includes a programmer, in someembodiments. In the illustrated embodiment, the external system includesa patient management system. As illustrated, the external system 2486 isa patient management system including an external device 2487, atelecommunication network 2488, and a remote device 2489. The externaldevice 2487 is placed within the vicinity of an implantable medicaldevice (IMD) and includes an external telemetry system 2490 tocommunicate with the 1 MB. The remote device(s) 2489 is in one or moreremote locations and communicates with the external device 2487 throughthe network 2488, thus allowing a physician or other caregiver tomonitor and treat a patient from a distant location and/or allowingaccess to various treatment resources from the one or more remotelocations. The illustrated remote device 2489 includes a user interface2491. According to various embodiments, the external device 2487includes a neural stimulator, a programmer or other device such as acomputer, a personal data assistant or phone. The external device 2487,in various embodiments, includes two devices adapted to communicate witheach other over an appropriate communication channel. The externaldevice can be used by the patient or physician to provide side effectfeedback indicative of patient discomfort, for example.

Therapies

The present subject matter relates to systems, devices and methods forproviding neural stimulation, such as vagus nerve stimulation, andfurther relates to delivering neural stimulation therapy (NST) or vagalnerve modulation (VNM) with a stimulation signal at a locationdetermined to provide a desired transient evoked response to thestimulus. The present subject matter can be applied to neurostimulationtherapies used to treat cardiovascular diseases, such as heart failure,tachyarrhythmia, hypertension, and atherosclerosis. Various embodimentsprovide a stand-alone device, either externally or internally, toprovide neural stimulation therapy. The present subject matter can beimplemented in cardiac applications for neural stimulation or innon-cardiac applications for neural stimulation where a diverse nerve(such as the vagus nerve) is stimulated. For example, the presentsubject matter may deliver anti-remodeling therapy through neuralstimulation as part of a post-MI or heart failure therapy. Variousembodiments provide systems or devices that integrate neural stimulationwith one or more other therapies, such as bradycardia pacing,anti-tachycardia therapy, remodeling therapy, and the like.

Neural Stimulation Therapies

Examples of neural stimulation therapies include neural stimulationtherapies for respiratory problems such a sleep disordered breathing,for blood pressure control such as to treat hypertension, for cardiacrhythm management, for myocardial infarction and ischemia, for heartfailure, for epilepsy, for depression, for pain, for migraines, foreating disorders and obesity, for movement disorders, for cardiovasculardisease, for metabolic disease, for inflammatory disease and foratherosclerosis. Many proposed neural stimulation therapies includestimulation of an autonomic neural target such as the vagus nerve. Thislisting of other neural stimulation therapies is not intended to be anexhaustive listing. Neural stimulation can be provided using electrical,acoustic, ultrasound, light, and magnetic therapies. Electrical neuralstimulation can be delivered using any of a nerve cuff,intravascularly-fed lead, or transcutaneous electrodes.

Various embodiments of the present subject matter deliver vagal nervemodulation (VNM) to treat a variety of cardiovascular disorders,including heart failure, post-MI remodeling, and hypertension. Theseconditions are briefly described below.

Heart failure refers to a clinical syndrome in which cardiac functioncauses a below normal cardiac output that can fall below a leveladequate to meet the metabolic demand of peripheral tissues. Heartfailure may present itself as congestive heart failure (CHF) due to theaccompanying venous and pulmonary congestion. Heart failure can be dueto a variety of etiologies such as ischemic heart disease.

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure, which can contribute to heart failure. Hypertension generallyrelates to high blood pressure, such as a transitory or sustainedelevation of systemic arterial blood pressure to a level that is likelyto induce cardiovascular damage or other adverse consequences.Hypertension has been defined as a systolic blood pressure above 140 mmHg or a diastolic blood pressure above 90 mm Hg. Consequences ofuncontrolled hypertension include, but are not limited to, retinalvascular disease and stroke, left ventricular hypertrophy and failure,myocardial infarction, dissecting aneurysm, and renovascular disease.

Cardiac remodeling refers to a complex remodeling process of theventricles that involves structural, biochemical, neurohormonal, andelectrophysiologic factors, which can result following a myocardialinfarction (MI) or other cause of decreased cardiac output. Ventricularremodeling is triggered by a physiological compensatory mechanism thatacts to increase cardiac output due to so-called backward failure whichincreases the diastolic filling pressure of the ventricles and therebyincreases the so-called preload (i.e., the degree to which theventricles are stretched by the volume of blood in the ventricles at theend of diastole). An increase in preload causes an increase in strokevolume during systole, a phenomena known as the Frank-Starlingprinciple. When the ventricles are stretched due to the increasedpreload over a period of time, however, the ventricles become dilated.The enlargement of the ventricular volume causes increased ventricularwall stress at a given systolic pressure. Along with the increasedpressure-volume work done by the ventricle, this acts as a stimulus forhypertrophy of the ventricular myocardium. The disadvantage ofdilatation is the extra workload imposed on normal, residual myocardiumand the increase in wall tension (Laplace's Law) which represent thestimulus for hypertrophy. If hypertrophy is not adequate to matchincreased tension, a vicious cycle ensues which causes further andprogressive dilatation. As the heart begins to dilate, afferentbaroreceptor and cardiopulmonary receptor signals are sent to thevasomotor central nervous system control center, which responds withhormonal secretion and sympathetic discharge. The combination ofhemodynamic, sympathetic nervous system and hormonal alterations (suchas presence or absence of angiotensin converting enzyme (ACE) activity)account for the deleterious alterations in cell structure involved inventricular remodeling. The sustained stresses causing hypertrophyinduce apoptosis (i.e., programmed cell death) of cardiac muscle cellsand eventual wall thinning which causes further deterioration in cardiacfunction. Thus, although ventricular dilation and hypertrophy may atfirst be compensatory and increase cardiac output, the processesultimately result in both systolic and diastolic dysfunction. It hasbeen shown that the extent of ventricular remodeling is positivelycorrelated with increased mortality in post-MI and heart failurepatients.

Sympathetic activity is pathologically elevated in HF and detrimentalover the long term. This situation is characterized by excessive releaseof norepinephrine (NE), so much so that myocardial adrenergic receptorsare down-regulated as the heart tries to protect itself from theexcessive myocardial infarction (MI). A drug strategy augments thisprotective response by blocking the remaining myocardial adrenergicreceptors. However, parasympathetic activity is actively depressed inheart failure (HF), and this depressed parasympathetic activity haslargely been ignored for HF treatment. In particular, acetylcholine(ACh) release in the heart is presynaptically inhibited by angiotensinII, which is markedly elevated in HF. In response to this lack of ACh,the myocardial muscarinic receptors are markedly upregulated to try toincrease the effects of ACh. Also parasympathetic reflexes, such as thebaroreceptor reflex, are inhibited by the increased sympatheticactivity.

The vagus nerve can be stimulated in the cervical region with implantednerve cuff electrodes attached via a lead to an implanted pulsegenerator in the chest. Based on preclinical studies, this VNM has beenfound to prevent left ventricular dilatation and improve pump function(left ejection fraction) when administered for three months followinginduction of HF by microembolism in dogs. Thus, VNM may be a treatmentfor HF disease and symptoms. It is believed that VNM may counterbalancethe depressed parasympathetic levels that occur during HF. The VNM thatwas successful in the preclinical studies at treating the HF wasadministered with periods of approximately 10 second stimulation burstsonce every minute. The stimulation during the burst was a series ofelectrical pulses around 1 mA and around 20 Hz. In other words, thestimulation protocol includes intermittent bursts (e.g. 10 secondbursts) of stimulation. Each burst includes a plurality of pulsesdelivered at a pulse frequency (e.g. 20 Hz) during the burst (e.g.throughout the 10 second burst). The burst of pulses also may bedelivered at a burst frequency (e.g. 1 burst/60 seconds) if the burststimulation period of one minute is used. VNM can modulateparasympathetic cardiovascular activity, as indicated by the measuredeffects of this stimulation on heart rate (HR) and blood pressure (BP).

FIGS. 25-27 illustrate preclinical study results. In FIG. 25, HR (RRinterval) and BP (systolic pressure) recordings are shown from a sheepstimulated with the above VNM protocol. The example shows thatintermittent VNM can elicit periodic oscillations of HR and BP withoutchanging mean HR and BP. The upper panel shows HR and BP responses to aseries of five 10 second bursts of vagal stimulation (VS) separated by50 seconds of no stimulation. The lower panel shows the signal averagedHR and BP responses for the one minute intermittent stimulation period.The direct effect of the stimulation decreases the BP, which in turnelicits a reflex response that transiently increases the HR (decreasesthe R-to-R heart beat interval as shown on the graph). As the directstimulation ends, BP rebounds and increases above baseline due to areflex response to the directly decreased BP. These HR and BPoscillations are allowed to wash out before the next stimulation suchthat there is not a significant change in the average heart rate orblood pressure over the intermittent stimulation period (e.g. 10 secondstimulation bursts separated by 50 seconds of no stimulation). These HRand BP oscillations are the result of directly and reflexivelymodulating ANS activity. FIG. 26 illustrates changes in the HR (RRinterval) and systolic BP over a 30 minute period while stimulating thevagus with a 10 second burst every 60 seconds. Every minute, the RRinterval oscillates+7 bpm around a randomly fluctuating mean, andcorrespondingly, systolic BP oscillates about +7 mmHg around a randomlyfluctuating mean. The fluctuations in HR and BP means are uncorrelatedwith the intermittent neural stimulation, and rather reflect naturalinfluences on HR and BP that have a different time scale than thestimulation period. FIG. 27 shows the Fast Fourier Transform powerspectrum of the BP signal, which indicates that the signal is dominatedby a once-per-minute (60 second period) modulation corresponding to theVNM duty cycle of a 10 second burst every minute.

When a neural stimulation therapy is delivered with a step up to thetherapeutic intensity at the beginning of a duty cycle, and a step downat the end of the duty cycle, transients have been observed in theneurological system. For example, abrupt changes in parasympatheticneural stimulation intensity can result in a sympathetic tone rebound.For example, upon conclusion of a stimulation pulse train that elicits aparasympathetic response, there is sympathetic tone rebound that isreflected in increased HR and increased BP. Possible mechanisms involvedwith the observed rebound may include the activation of the baroreflexand/or chemoreflex.

In the preclinical study illustrated in FIGS. 25-27, it is believed thatthe VNM device and protocol are directly decreasing BP for the 10seconds it is on (bursting). This triggers baroreceptor signalsindicating that BP should be increased, which elicits a reflexsympathetic activation that increases HR. After the direct NS responseends, the sympathetic activation also increases BP. The baroreceptorsrespond again, now to the increased BP, and elicit a reflexparasympathetic activation that decreases HR and BP back towardbaseline. The reflex-mediated oscillations of HR and BP are allowed towash out before the next stimulation. Various embodiments of the presentsubject matter intermittently or periodically stimulate ANS cardiacactions both directly and reflexively and without changing orsignificantly altering mean HR or BP. Various embodiments can eitherdirectly stimulate parasympathetic actions or sympathetic actions orboth kinds of actions.

Some embodiments deliver direct and reflex (e.g., baroreceptor reflex)stimulation of the cardiovascular parasympathetic neural pathways withone vagus nerve stimulation site/lead. One embodiment in this caseselectively stimulates the vagus nerve cardiac efferent (motoneuron)axons that have a direct effect on HR and/or BP. In some embodiments,the duration and magnitude of a stimulation burst is timed to activatebaroreceptor reflexes that have an equal magnitude but opposite effecton HR and BP. Another embodiment selectively stimulates the vagus nerveafferent axons that directly activate central nervous system networkscontrolling BP, causing BP to oscillate during and after the VNMstimulation burst and indirectly causing HR to oscillate reflexively inresponse to the BP oscillations.

A therapy embodiment involves preventing and/or treating ventricularremodeling. Activity of the autonomic nervous system is at least partlyresponsible for the ventricular remodeling which occurs as a consequenceof an MI or due to heart failure. It has been demonstrated thatremodeling can be affected by pharmacological intervention with the useof, for example, ACE inhibitors and beta-blockers. Pharmacologicaltreatment carries with it the risk of side effects, however, and it isalso difficult to modulate the effects of drugs in a precise manner.Embodiments of the present subject matter employ electrostimulatorymeans to modulate autonomic activity, referred to as anti-remodelingtherapy or ART. When delivered in conjunction with ventricularresynchronization pacing, also referred to as remodeling control therapy(RCT), such modulation of autonomic activity may act synergistically toreverse or prevent cardiac remodeling.

One neural stimulation therapy embodiment involves treating hypertensionby stimulating the baroreflex for sustained periods of time sufficientto reduce hypertension. The baroreflex is a reflex that can be triggeredby stimulation of a baroreceptor or an afferent nerve trunk. Baroreflexneural targets include any sensor of pressure changes (e.g. sensorynerve endings that function as a baroreceptor) that is sensitive tostretching of the wall resulting from increased pressure from within,and that functions as the receptor of the central reflex mechanism thattends to reduce that pressure. Baroreflex neural targets also includeneural pathways extending from the baroreceptors. Baroreflex neuraltargets can be found in the wall of the auricles of the heart, cardiacfat pads, vena cava, aortic arch and carotid sinus. Examples of afferentnerve trunks that can serve as baroreflex neural targets include thevagus, aortic and carotid nerves. Stimulating baroreceptors inhibitssympathetic nerve activity (stimulates the parasympathetic nervoussystem) and reduces systemic arterial pressure by decreasing peripheralvascular resistance and cardiac contractility. Baroreceptors arenaturally stimulated by internal pressure and the stretching of thearterial wall. Chemoreceptors, which are sensory nerve cells thatrespond to chemical stimuli, may be stimulated to stimulate a desiredautonomic reflex response. Some aspects of the present subject matterlocally stimulate specific nerve endings in arterial walls rather thanstimulate afferent nerve trunks in an effort to stimulate a desiredresponse (e.g. reduced hypertension) while reducing the undesiredeffects of indiscriminate stimulation of the nervous system. Forexample, some embodiments stimulate baroreceptor sites in the pulmonaryartery. Some embodiments of the present subject matter involvestimulating either baroreceptor sites or nerve endings in the aorta, thechambers of the heart, the fat pads of the heart, and some embodimentsof the present subject matter involve stimulating an afferent nervetrunk, such as the vagus, carotid and aortic nerves. Some embodimentsstimulate afferent or efferent nerve trunks using a cuff electrode, andsome embodiments stimulate afferent nerve trunks using an intravascularlead positioned in a blood vessel proximate to the nerve, such that theelectrical stimulation passes through the vessel wall to stimulate theafferent nerve trunk.

Neural stimulation (e.g. sympathetic nerve stimulation and/orparasympathetic nerve inhibition) can mimic the effects of physicalconditioning. It is generally accepted that physical activity andfitness improve health and reduce mortality. Studies have indicated thataerobic training improves cardiac autonomic regulation, reduces heartrate and is associated with increased cardiac vagal outflow. A baselinemeasurement of higher parasympathetic activity is associated withimproved aerobic fitness. Exercise training intermittently stresses thesystem and increases the sympathetic activity during the stress.However, when an exercise session ends and the stress is removed, thebody rebounds in a manner that increases baseline parasympatheticactivity and reduces baseline sympathetic activity. Physicalconditioning can be considered to be a repetitive, high-level exercisethat occurs intermittently over time. Physical conditioning therapy canbe applied as therapy for heart failure. Examples of other physicalconditioning therapies include therapies for patients who are unable toexercise. For example, physical conditioning using sympatheticstimulation/parasympathetic inhibition for a bed-bound, post-surgicalpatient in a hospital may enable the patient to maintain strength andendurance until such time that the patient is able to exercise again. Byway of another example, a morbidly obese patient may be unable toexercise, but may still benefit from the physical conditioning therapy.Furthermore, patients with injuries such as joint injuries that preventthem from performing their normal physical activities may benefit fromthe physical conditioning therapy.

Embodiments described herein can be used to treat diseases associatedwith depressed parasympathetic levels and activity in patientsintolerant of tonic decreases in heart rate or blood pressure. Examplesof such diseases associated with depressed parasympathetic levelsinclude HF, MI, tachyarrhythmia, hypertension, atherosclerosis. Becausemean HR and BP are not significantly altered using the stimulationprotocol that drives oscillations in HR and BP, the device providesbeneficial results of increased parasympathetic tone while avoidingpotential side-effects of previous devices and methods for vagalstimulation, which can cause bradycardia and hypotension. For example,an embodiment increases heart rate variability (HRV) (or otherindicators of autonomic tone) without changing mean HR. This may bebeneficial in patients with reduced HRV, such as advanced HF patients,who are also on medications that already lower their HR.

An embodiment includes an implantable vagus nerve stimulator fortreatment of cardiovascular diseases associated with depressedparasympathetic levels, such as HF. An embodiment intermittently orperiodically (e.g. once per minute) increases parasympathetic levels andactions by direct parasympathetic nerve stimulation and reflexactivation of evoked parasympathetic responses in a way that modulatesHR and BP during the periodic stimulation without changing orsignificantly altering the mean HR or BP. That is, the device deliversstimulation to efferent pathways to provide the direct response, andalso delivers stimulation to afferent pathways to induce a reflexresponse. Some devices are capable of independently controlling theefferent and afferent stimulation. This provides a dual therapy (directand reflex parasympathetic activation) that is safe for patients at riskof bradycardia or hypotension from vagus nerve stimulation.

An embodiment includes an implantable vagus nerve stimulator adapted toincrease parasympathetic levels and activity with intermittent orperiodic (e.g., on the order of 10 seconds once per minute) modulatorystimulation that is associated with periodic HR and BP oscillationswithout significantly altering mean HR or mean BP over an approximatelyone minute time scale.

Myocardial Stimulation Therapies

Various neural stimulation therapies can be integrated with variousmyocardial stimulation therapies. The integration of therapies may havea synergistic effect. Therapies can be synchronized with each other, andsensed data can be shared between the therapies. A myocardialstimulation therapy provides a cardiac therapy using electricalstimulation of the myocardium. Some examples of myocardial stimulationtherapies are provided below.

A pacemaker is a device which paces the heart with timed pacing pulses,most commonly for the treatment of bradycardia where the ventricularrate is too slow. If functioning properly, the pacemaker makes up forthe heart's inability to pace itself at an appropriate rhythm in orderto meet metabolic demand by enforcing a minimum heart rate. Implantabledevices have also been developed that affect the manner and degree towhich the heart chambers contract during a cardiac cycle in order topromote the efficient pumping of blood. The heart pumps more effectivelywhen the chambers contract in a coordinated manner, a result normallyprovided by the specialized conduction pathways in both the atria andthe ventricles that enable the rapid conduction of excitation (i.e.,depolarization) throughout the myocardium. These pathways conductexcitatory impulses from the sino-atrial node to the atrial myocardium,to the atrio-ventricular node, and thence to the ventricular myocardiumto result in a coordinated contraction of both atria and bothventricles. This both synchronizes the contractions of the muscle fibersof each chamber and synchronizes the contraction of each atrium orventricle with the contralateral atrium or ventricle. Without thesynchronization afforded by the normally functioning specializedconduction pathways, the heart's pumping efficiency is greatlydiminished. Pathology of these conduction pathways and otherinter-ventricular or intra-ventricular conduction deficits can be acausative factor in heart failure, which refers to a clinical syndromein which an abnormality of cardiac function causes cardiac output tofall below a level adequate to meet the metabolic demand of peripheraltissues. In order to treat these problems, implantable cardiac deviceshave been developed that provide appropriately timed electricalstimulation to one or more heart chambers in an attempt to improve thecoordination of atrial and/or ventricular contractions, termed cardiacresynchronization therapy (CRT). Ventricular resynchronization is usefulin treating heart failure because, although not directly inotropic,resynchronization can result in a more coordinated contraction of theventricles with improved pumping efficiency and increased cardiacoutput. Currently, a common form of CRT applies stimulation pulses toboth ventricles, either simultaneously or separated by a specifiedbiventricular offset interval, and after a specified atrio-ventriculardelay interval with respect to the detection of an intrinsic atrialcontraction or delivery of an atrial pace.

CRT can be beneficial in reducing the deleterious ventricular remodelingwhich can occur in post-MI and heart failure patients. Presumably, thisoccurs as a result of changes in the distribution of wall stressexperienced by the ventricles during the cardiac pumping cycle when CRTis applied. The degree to which a heart muscle fiber is stretched beforeit contracts is termed the preload, and the maximum tension and velocityof shortening of a muscle fiber increases with increasing preload. Whena myocardial region contracts late relative to other regions, thecontraction of those opposing regions stretches the later contractingregion and increases the preload. The degree of tension or stress on aheart muscle fiber as it contracts is termed the afterload. Becausepressure within the ventricles rises rapidly from a diastolic to asystolic value as blood is pumped out into the aorta and pulmonaryarteries, the part of the ventricle that first contracts due to anexcitatory stimulation pulse does so against a lower afterload than doesa part of the ventricle contracting later. Thus a myocardial regionwhich contracts later than other regions is subjected to both anincreased preload and afterload. This situation is created frequently bythe ventricular conduction delays associated with heart failure andventricular dysfunction due to an MI. The increased wall stress to thelate-activating myocardial regions is most probably the trigger forventricular remodeling. By pacing one or more sites in a ventricle nearthe infarcted region in a manner which may cause a more coordinatedcontraction, CRT provides pre-excitation of myocardial regions whichwould otherwise be activated later during systole and experienceincreased wall stress. The pre-excitation of the remodeled regionrelative to other regions unloads the region from mechanical stress andallows reversal or prevention of remodeling to occur.

Cardioversion, an electrical shock delivered to the heart synchronouslywith the QRS complex, and defibrillation, an electrical shock deliveredwithout synchronization to the QRS complex, can be used to terminatemost tachyarrhythmias. The electric shock terminates the tachyarrhythmiaby simultaneously depolarizing the myocardium and rendering itrefractory. A class of CRM devices known as an implantable cardioverterdefibrillator (ICD) provides this kind of therapy by delivering a shockpulse to the heart when the device detects tachyarrhythmias. Anothertype of electrical therapy for tachycardia is anti-tachycardia pacing(ATP). In ventricular ATP, the ventricles are competitively paced withone or more pacing pulses in an effort to interrupt the reentrantcircuit causing the tachycardia. Modern ICDs typically have ATPcapability, and deliver ATP therapy or a shock pulse when atachyarrhythmia is detected.

Some embodiments provide a NS device configured to communicate, eitherwired or wireless, with other implantable devices that have sensors formeasuring short and long term physiological responses of theneurostimulation. These responses can be used to measure the transientresponse and to measure clinical responses.

One of ordinary skill in the art will understand that, the modules andother circuitry shown and described herein can be implemented usingsoftware, hardware, firmware and combinations thereof.

The above detailed description is intended to be illustrative, and notrestrictive. Other embodiments will be apparent to those of skill in theart upon reading and understanding the above description. The scope ofthe invention should, therefore, be determined with reference to theappended claims, along with the full scope of equivalents to which suchclaims are entitled.

1. (canceled)
 2. A method comprising: delivering doses of neuralstimulation therapy, wherein delivering each of the doses includesdelivering a pulse train of more than one neural stimulation pulse,wherein successively delivered doses are separated by a time when neuralstimulation is not delivered; sensing transient evoked responses innerve traffic between the doses of neural stimulation therapy during thetime when neural stimulation is not delivered; and performing a at leastone action using the sensed transient evoked responses, the at least oneaction including: changing the doses of the neural stimulation therapybased on the sensed transient evoked responses in the nerve traffic, orrecording data corresponding to the sensed transient evoked responses inthe nerve traffic.
 3. The method of claim 2, wherein the more than oneneural stimulation pulse of the pulse train is delivered with a pulseperiod, and the successively delivered doses are separated by more thanone pulse period.
 4. The method of claim 2, wherein the doses of neuralstimulation therapy have a burst period, and the pulse train has aduration less than the burst period.
 5. The method of claim 2, whereinthe changing the doses includes changing a stop time of the pulse trainbased on the sensed transient evoked responses.
 6. The method of claim2, wherein the changing the doses includes changing an end time of thepulse train based on the sensed transient evoked responses.
 7. Themethod of claim 2, wherein the changing the doses includes changing anumber of pulses in the pulse train based on the sensed transient evokedresponses.
 8. The method of claim 2, wherein the changing the dosesincludes changing a pulse amplitude based on the sensed transient evokedresponses.
 9. The method of claim 2, wherein the changing the dosesincludes changing a pulse width based on the sensed transient evokedresponses.
 10. The method of claim 2, wherein the changing the dosesincludes changing a pulse frequency based on the sensed transient evokedresponses.
 11. The method of claim 2, wherein each pulse train is aburst, and the changing the doses includes changing a burst duty cyclebased on the sensed transient evoked responses.
 12. The method of claim2, wherein the delivering doses includes using a programmed schedule tocontrol delivery of each pulse train.
 13. The method of claim 2, furthercomprising sensing nerve traffic responses during delivery of the pulsetrain, and the performing the action includes using both the nervetraffic responses during the delivering of the pulse train and thetransient evoked responses in nerve traffic between the doses of neuralstimulation therapy during the time when neural stimulation is notdelivered.
 14. The method of claim 2, further comprising performing astatistical analysis of the transient evoked responses, wherein theperforming the action using the sensed transient evoked responsesincludes changing the doses based on the statistical analysis, orrecording statistical analysis data for access by a clinician.
 15. Anon-transitory machine-readable medium including instructions, whichwhen executed by a machine, cause the machine to: deliver doses ofneural stimulation therapy, wherein each of the doses includes a pulsetrain of more than one neural stimulation pulse, wherein successivelydelivered doses are separated by a time when neural stimulation is notdelivered; sense transient evoked responses in nerve traffic between thedoses of neural stimulation therapy during the time when neuralstimulation is not delivered; and perform at least one action using thesensed transient evoked responses, the at least one action including:change the doses of the neural stimulation therapy based on the sensedtransient evoked responses in the nerve traffic, or record datacorresponding to the sensed transient evoked responses in the nervetraffic.
 16. The non-transitory machine-readable of claim 15, whereinthe instructions include instructions, which when executed by themachine, cause the machine to use a programmed schedule to controldelivery of each pulse train.
 17. The non-transitory machine-readable ofclaim 15, wherein the instructions include instructions, which whenexecuted by the machine, cause the machine to sense nerve trafficresponses during delivery of the pulse train, and perform the actionusing both the nerve traffic responses during the delivering of thepulse train and the transient evoked responses in nerve traffic betweenthe doses of neural stimulation therapy during the time when neuralstimulation is not delivered.
 18. A system, comprising: a neuralstimulator; a controller configured to cooperate with the neuralstimulator to deliver doses of neural stimulation therapy, wherein eachof the doses includes a pulse train of more than one neural stimulationpulse, wherein successively delivered doses are separated by a time whenneural stimulation is not delivered; and a sensor configured to sensetransient evoked responses in nerve traffic between the doses of neuralstimulation therapy during the time when neural stimulation is notdelivered, wherein the controller is configured to perform at least oneaction using the sensed transient evoked responses, the at least oneaction including: change the doses of the neural stimulation therapybased on the sensed transient evoked responses in the nerve traffic, orrecord data corresponding to the sensed transient evoked responses inthe nerve traffic.
 19. The system of claim 18, wherein the controller isconfigured to use a programmed schedule to control delivery of eachpulse train.
 20. The system of claim 18, wherein the sensor isconfigured to sense nerve traffic responses during delivery of the pulsetrain, and the controller is configured to perform the action using boththe nerve traffic responses during the delivering of the pulse train andthe transient evoked responses in nerve traffic between the doses ofneural stimulation therapy during the time when neural stimulation isnot delivered.
 21. The system of claim 18, wherein the controller isconfigured to perform a statistical analysis of the transient evokedresponses, and perform at least one of: change the doses based on thestatistical analysis, or record statistical analysis data for access bya clinician.